Search Results (114,560)

Lutetium-177-PSMA-617 (Lu-PSMA) radioligand therapy (RLT) is established in metastatic castration-resistant prostate cancer (mCRPC), with regulatory approvals based on the VISION and TheraP trials. Subsequent trials have extended the evidence to taxane-naive mCRPC (PSMAfore) and demonstrated that combining Lu-PSMA with enzalutamide yields a significant overall survival benefit over enzalutamide alone (ENZA-p). However, higher and more homogeneous PSMA expression in treatment-naive disease, combined with lower tumor burden and preserved bone marrow reserve, provides a biological rationale for deploying RLT earlier in the disease course. In metastatic hormone-sensitive prostate cancer (mHSPC), the Phase III PSMAddition trial reported improved radiographic progression-free survival when Lu-PSMA was added to standard androgen deprivation therapy (ADT) plus androgen receptor pathway inhibitor (ARPI), and the Phase II UpFrontPSMA trial demonstrated enhanced biochemical responses with Lu-PSMA induction before docetaxel. In oligometastatic and oligorecurrent disease, the BULLSEYE and LUNAR trials have shown progression-free survival benefits, raising the possibility of deferring androgen deprivation therapy and its associated morbidity. Meanwhile, next-generation radionuclides, including actinium-225 (WARMTH) and the dual beta-Auger emitter terbium-161 (VIOLET), are entering clinical development to address the radiobiological limitations of Lutetium-177. This review synthesizes the evidence for PSMA-targeted radioligand therapy across the prostate cancer disease continuum and discusses patient selection, treatment sequencing, and the access and cost-effectiveness considerations that will shape adoption in earlier disease settings. Full article

Parkinson’s disease (PD), impacting millions worldwide, leads to motor deficits and various non-motor symptoms. Although there is no cure, treatment primarily involves dopamine replacement therapy, especially L-dopa for motor symptoms, and additional drugs are required to address non-motor effects. This underscores the increasing demand for dual-acting drugs that can effectively target both symptom types in PD. This study explored the potential effects of a standardised Mesembryanthemum tortuosum extract, Zembrin^®, in treating PD, utilising in vivo and in silico models. Zebrafish larvae were subjected to pre-treatment with reserpine, followed by exposure to Zembrin^®, with selegiline and L-dopa as positive controls. The in vivo component of this study monitored locomotion and oxidative stress, while the in silico component identified potential drug targets for the treatment of PD. Reserpine induced hypolocomotion and oxidative stress in zebrafish larvae, and Zembrin^® (12.5 µg/mL) effectively enhanced locomotion and reduced oxidative stress. The molecular docking, molecular dynamics simulations, and binding free energy calculations revealed that four mesembrine alkaloids (mesembranol, mesembrenol, mesembrenone, and mesembrine) form stable and energetically favourable complexes with monoamine oxidase B (MAO-B) and dopamine transporter (DAT), which are significant targets for addressing both the motor and non-motor effects of PD. Full article

Hypogonadism is increasingly recognized as an independent cardiovascular risk factor, with testosterone deficiency associated with endothelial dysfunction, increased thrombotic risk, and adverse cardiovascular outcomes. Circulating biomarkers provide valuable insights into the vascular health status of hypogonadal men and the cardiovascular effects of testosterone replacement therapy (TRT). This comprehensive review examines the molecular basis of testosterone action on the cardiovascular system and synthesizes evidence on circulating cardiovascular biomarkers in hypogonadism, including endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), platelet markers, endothelial activators, adhesion molecules, and inflammatory/oxidative stress markers. We also compare the cardiovascular safety profiles of transdermal versus intramuscular testosterone formulations. Hypogonadal men exhibit reduced circulating EPCs, elevated EMPs, increased platelet reactivity, higher levels of endothelial activators (ICAM-1, VCAM-1, E-selectin, von Willebrand factor, endothelin-1, ADMA), and increased inflammatory markers (hsCRP, IL-6, TNF-α). TRT improves most of these biomarkers through androgen receptor (AR)-dependent and AR-independent mechanisms involving PI3K/Akt/eNOS signaling, VEGF upregulation, CXCL12/CXCR4 axis modulation, and NF-κB pathway suppression. Current evidence suggests that transdermal testosterone formulations may offer advantages regarding hematological safety and more stable testosterone exposure; however, definitive evidence demonstrating superior cardiovascular outcomes compared with intramuscular formulations remains limited. Circulating cardiovascular biomarkers are significantly altered in hypogonadism and improve with TRT. Available data suggest that transdermal testosterone formulations may offer a more favorable cardiovascular safety profile than intramuscular preparations, particularly with respect to erythrocytosis and pharmacokinetic stability, although head-to-head randomized trials with hard cardiovascular endpoints are still needed. Understanding the molecular mechanisms underlying these changes is essential for optimizing TRT in hypogonadal men with cardiovascular risk factors. The cardiovascular safety advantage of transdermal formulations is currently supported primarily by pharmacokinetic and hematological evidence; direct comparative evidence from randomized trials with hard cardiovascular endpoints remains unavailable. Full article

Background and Objectives: Burning Mouth Syndrome (BMS) remains a challenging condition to manage, as current treatments show variable efficacy and are often limited by tolerability, particularly in older and medically complex patients. This has prompted interest in topical neuromodulatory strategies targeting peripheral mechanisms while minimizing systemic exposure, with topical pregabalin emerging as a potential option. Materials and Methods: In this prospective longitudinal real-world study, 100 patients with BMS treated at a tertiary referral center received topical pregabalin as an off-label intraoral swish-and-spit solution. Patients were assessed at baseline and after 3 months using validated measures of pain intensity (VAS), qualitative pain perception (SF-MPQ), anxiety (HAM-A), depression (HAM-D), sleep quality (PSQI, ESS), and global clinical severity (CGI-S). Results: After 3 months, median VAS decreased from 8 (IQR 7–9) to 5 (IQR 4–6) and SF-MPQ from 10 (IQR 7–17) to 6.5 (IQR 4–10) (both p < 0.001), with concurrent improvements in anxiety, depressive symptoms, and clinical severity. Overall, 46% of patients achieved ≥30% pain reduction, while 73% and 16% reached ≥20% and ≥50% reductions, respectively. Higher baseline pain predicted greater improvement. No serious adverse events were reported. Conclusions: These findings suggest that topical pregabalin may represent a safe and potentially effective option for BMS, although controlled studies are required to confirm its efficacy. Full article

The evaluation of stents in coronary computed tomography angiography (CCTA) is still a major topic in cardiovascular imaging. Using Photon-Counting Detector CT (PCCT) may improve the assessment of coronary stents and make on-site CT-FFR analysis feasible for ruling out in-stent restenosis (ISR). In this study, patients with previous coronary stent implantation who underwent CCTA using PCCT and subsequent invasive catheter angiography (ICA) were included. Stent characteristics such as location and length were reported. CT-FFR measurements were taken 1.8 cm before and after the stent, with a value of ≤0.80 defined as hemodynamically significant under respecting the diagnostic accuracy drop in the gray zone between 0.76 and 0.80. Delta CT-FFR with a cut-off value of ≥0.06, indicating hemodynamic significance, was determined. Any ISR and interventional treatment during the following ICA was recorded. Diagnostic performance metrics, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were calculated for post-stent CT-FFR and Delta CT-FFR in detecting ISR. Patients were followed up to evaluate the rate of major adverse cardiovascular events (MACE) 6 months after CCTA. A total of 19 patients (5 female, 14 male, median age 69 years) were enrolled in this study. In most cases, coronary stents were located in the proximal LAD with a median stent length of 70.2 mm. Pathological CT-FFR < 0.76 distal to the stent was detected in 6 cases (31.6%), while pathological Delta CT-FFR ≥ 0.06 occurred in 14 cases (73.7%). ICA was performed in three of these patients, with ISR confirmed in two cases. These findings yield sensitivity and NPV of 100% for both post-stent CT-FFR and Delta CT-FFR for excluding ISR with a superior specificity (76.5% vs. 29.4%) and overall diagnostic accuracy (78.9% vs. 36.8%) for post-stent CT-FFR. Two patients reported a myocardial infarction in follow-up; however, neither of them was located in the territory of the stented coronary artery. This study outlines the feasibility of on-site CT-FFR analysis using PCCT in excluding ISR in coronary stents with a high diagnostic accuracy. These findings highlight the need to extend the benefits of CT-FFR analysis for non-invasive assessment of possible ISR regarding personalized risk stratification and therapy planning. Full article

Early engagement with psychotherapy is a public mental health issue because potential patients’ first appraisals of psychological care may shape treatment expectations, willingness to continue, and openness to receiving effective support. In first-contact therapeutic encounters, people respond not only to the content of a therapist’s intervention but also to the interpersonal meaning conveyed by the therapist’s response style. Guided by a recognition–resistance framework and models of narcissistic self-regulation, we examined how therapist response style and trait narcissistic admiration and rivalry shape early appraisals of psychological care in a vignette-based psychotherapeutic encounter. In a between-subjects vignette experiment, Hebrew-speaking adults in Israel (N = 972) were randomly assigned to read a validation-based, recognition-supportive, autonomy-supportive therapist response or a more directive and challenging response to the same clinical scenario. Participants then reported perceived recognition, autonomy-related resistance, anticipated alliance, therapist credibility, expected benefit, and willingness to continue. The validation-based response elicited higher perceived recognition, lower autonomy-related resistance, and greater willingness to continue. Perceived recognition and autonomy-related resistance mediated the effects of response style on all therapy-related outcomes. Narcissistic admiration predicted more favorable appraisals, and narcissistic rivalry predicted lower recognition and greater resistance, but neither moderated style effects nor indirect pathways. Recognition and autonomy-related resistance emerged as proximal appraisal pathways linking therapist response style to anticipated engagement with psychological care in this analogue vignette context. However, the predicted moderation and moderated-mediation effects involving narcissistic admiration and rivalry were not supported. This pattern suggests that, in the present design, admiration and rivalry functioned more as general appraisal orientations than as differential-susceptibility moderators of therapist response style. The moderated-mediation component of the recognition–resistance framework should therefore be regarded as unsupported pending independent replication and more ecologically valid tests. These findings position first-contact therapist communication as a candidate modifiable feature of public mental health engagement, with implications for future research on treatment uptake, early retention, trust in services, and access to effective psychological care. Full article

Background: Low admission low-density lipoprotein cholesterol (LDL-C) is paradoxically associated with worse outcomes after acute coronary syndrome, but this may reflect confounding rather than causation. We examined the paradox in statin-naïve patients. Methods: We studied 388 statin-naïve patients with a first ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) and followed for up to five years. Admission LDL-C was analyzed continuously and as three categories (<100, 100–130, >130 mg/dL), with all-cause mortality assessed using Kaplan–Meier, Cox regression, restricted cubic splines, and landmark sensitivity analyses. Results: Crude mortality was highest in the lowest LDL-C group (20.0% vs. 8.3% vs. 10.7%; p = 0.014), and LDL-C < 100 mg/dL predicted higher mortality (hazard ratio 2.03, 95% CI 1.02–4.03). After adjustment, this remained non-significant across the parsimonious and fully adjusted models (adjusted HR 1.27–1.43, all 95% CIs including 1); older age, lower ejection fraction, and diabetes were independent predictors of death. The lowest stratum also had lower albumin and higher CONUT scores, consistent with a frailty phenotype. Conclusions: In statin-naïve STEMI patients undergoing primary PCI, the lipid paradox reflected age- and frailty-related confounding rather than protection; low admission LDL-C marks a higher-risk phenotype and should not discourage guideline-directed lipid-lowering therapy. Full article

Acute otitis media is an inflammatory disease affecting all compartments of the middle ear, characterized by localized pain, fever, hearing impairment, and, occasionally, purulent exudate. It represents a significant clinical concern in both pediatric and adult populations, with approximately 709 million cases reported annually worldwide, 51% of which occur in children. However, currently available topical otic formulations are limited by their inability to achieve predictable therapeutic concentrations at the site of inflammation, resulting in reduced efficacy. In addition, the selection of appropriate active pharmaceutical ingredients (APIs) for drug products remains challenging; as a result, existing therapies do not comprehensively address all stages of pathogenesis. This study aimed to analyze existing locally acting formulations for middle ear drug delivery, evaluate their advantages and limitations, and assess modern approaches to the development of novel drug delivery systems and API combinations. A critical review of 69 publications (2010–2026) was conducted, supplemented by a strengths and limitations analysis of dosage forms and an evaluation of APIs based on clinical data. The findings highlight a lack of targeted drug delivery systems, limited efficacy of existing API combinations against bacterial biofilms, and their risk of ototoxicity. Emerging innovative drug delivery approaches, including microemulsions, vesicular systems, stimuli-responsive systems, and hydrogels, have demonstrated promising results in preclinical studies; however, their efficacy and safety remain to be confirmed in clinical settings before their full therapeutic potential in otitis media treatment can be realized. Full article

Coronary in-stent restenosis (ISR) remains a major contributor to repeat revascularisation despite advances in drug-eluting stent (DES) technology. Its persistence reflects a complex and heterogeneous interplay among mechanical, biological, and procedural factors, and understanding the dominant mechanism in each case is fundamental to effective treatment selection. This narrative review provides a contemporary, mechanism-guided approach to the practical management of coronary ISR. We summarise the definition, incidence, and classification of ISR—including the Mehran, Waksman, and SCAI 2023 time-based frameworks—and outline patient-related, procedural, anatomical, and stent-related risk factors. The pathophysiology of neointimal hyperplasia and neoatherosclerosis is discussed with reference to its clinical implications. Intracoronary imaging with intravascular ultrasound (IVUS) or optical coherence tomography (OCT) is central to ISR characterisation and treatment planning. Current international guidelines support imaging use in ISR management, though it is important to recognise that this recommendation is based largely on observational and surrogate-endpoint data rather than ISR-specific randomised trials demonstrating reductions in hard clinical outcomes, and practical barriers including cost, availability, and operator expertise must be acknowledged. Evidence-based treatment strategies—including drug-coated balloons (DCB), repeat DES implantation, lesion-modifying therapies, vascular brachytherapy, and coronary artery bypass grafting—are reviewed critically with reference to contemporary trial data and their specific clinical applicability. The choice between DCB and repeat DES is addressed with greater nuance, accounting for ISR type (BMS-ISR versus DES-ISR), lesion pattern, stent layering, and bleeding risk. Management considerations in complex subsets—chronic total occlusion ISR, left main ISR, saphenous vein graft ISR, and recurrent ISR—are also addressed. We propose a practical, substrate-driven management framework aligned with the 2024 ESC, 2021 ACC/AHA/SCAI, and 2018 JCS/JSCVS guidelines. Future research priorities include ISR-specific randomised trials with hard clinical endpoints, prospective validation of imaging-guided treatment algorithms, head-to-head comparisons of DCB platforms, and investigation of pharmacological strategies targeting neoatherosclerosis progression. Full article

Background: Head and neck squamous cell carcinoma (HNSCC) remains a highly aggressive malignancy with poor clinical outcomes. Although poly(ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in tumors with homologous recombination deficiency, their efficacy in BRCA wild-type HNSCC remains limited. Reactive oxygen species (ROS)-induced DNA damage may increase cellular dependence on DNA repair pathways and thereby enhance sensitivity to PARP inhibition. This study investigated whether ROS-mediated DNA damage could sensitize BRCA wild-type HNSCC cells to the PARP inhibitor olaparib. Methods: BRCA wild-type HSC-3 and SCC-25 HNSCC cell lines were exposed to H₂O₂ to induce oxidative stress. Intracellular ROS levels were quantified using DCFDA assays, DNA double-strand breaks were evaluated by γ-H2AX ELISA, PARP activity was assessed by ELISA, and cell viability was determined using MTT assays. Expression levels of DNA repair genes (PARP1, PARP2, BRCA1, BRCA2, RAD51, and MLH1), checkpoint kinases (ATM, ATR, and CHK1), the homologous recombination regulator FANCD2, and redox defense genes (NQO1, GPX4, and SLC7A11) were analyzed by qRT-PCR. Therapeutic selectivity was assessed using HGF-1 normal human gingival fibroblasts as a normal cell control. Apoptosis was measured through caspase-3/7 activity assays, and drug interactions were evaluated using the Chou–Talalay method. Results: H₂O₂ treatment increased intracellular ROS levels in both cell lines, accompanied by significant induction of DNA damage as demonstrated by elevated γ-H2AX levels. ROS induction markedly enhanced olaparib sensitivity, significantly reducing IC₅₀ values in both HSC-3 and SCC-25 cells. Combined H₂O₂ and olaparib treatment produced strong synergistic cytotoxicity, suppressed DNA repair, checkpoint kinase, and redox defense gene expression, and increased caspase-3/7 activity compared with control cells. Importantly, the combination demonstrated selective cytotoxicity toward cancer cells, with normal HGF-1 cells retaining significantly higher viability. Conclusions: ROS-induced DNA damage significantly enhances the anti-tumor activity of olaparib in BRCA wild-type HNSCC cells through a functional synthetic lethal-like interaction involving the simultaneous collapse of DNA repair capacity, checkpoint activation, and oxidative stress buffering, culminating in apoptosis induction. These findings support the rationale for combining ROS-generating therapies with PARP inhibitors in HNSCC treatment. Full article

Background/Objectives: Curcumin shows broad anticancer activity but limited clinical success as a standalone agent because of poor bioavailability and inconsistent tumor exposure. This review introduces the concept of curcumin as a molecular synergy amplifier and proposes that successful combinations depend on three interdependent determinants: mechanistic complementarity, suppression of adaptive resistance networks, and pharmacokinetic synchronization. Methods: Evidence on combinations with chemotherapeutics, natural bioactives, and nanotechnology-enabled delivery systems was critically evaluated, with emphasis on mechanism, resistance reversal, drug ratio, administration sequence, and tumor exposure. Results: Curcumin enhances therapeutic efficacy by sensitizing cancer cells, suppressing adaptive resistance pathways, targeting cancer stemness, and promoting multiple forms of programmed cell death. Importantly, analysis of current evidence indicates that therapeutic success depends not only on molecular synergy but also on pharmacokinetic synchronization between curcumin and partner agents. Many combinations demonstrating strong in vitro synergy fail to translate in vivo because optimal drug ratios, timing, and tumor exposure cannot be maintained. Nanotechnology-based co-delivery systems partially overcome these limitations through synchronized delivery and controlled release. Conclusions: Curcumin should be viewed as a molecular synergy amplifier whose clinical utility depends on mechanistic complementarity and pharmacokinetic synchronization with co-administered therapies. This framework provides a rationale for the design of next-generation curcumin-based combination therapies and identifies key priorities for clinical translation. Full article

This qualitative study incorporates caregiver perspectives to identify their (1) experiences with medical and educational supports for their children with chronic TBI following inpatient rehabilitation and across the recovery trajectory and (2) recommendations to improve service provision for young people with TBI. Nineteen caregivers of children with complicated-mild-to-severe TBI participated in semi-structured virtual interviews. Participants were from a large Midwestern U.S. city. Researchers used reflexive thematic analysis, incorporating an experiential orientation and a deductive approach. Standards for Reporting Qualitative Research guided this process. Children were an average of 5.2 years post-injury, and age at injury ranged from 2.6 to 18.0 years, providing depth of caregiver experiences discussed in interviews. Four primary themes were identified: (1) TBI leads to lasting changes in the child, (2) the healthcare environment is overwhelming, (3) TBI forces a shift in caregiver responsibilities, and (4) school challenges persist over time. Caregivers generated concrete, experience-based recommendations, highlighting the need for increased support, resources, and education in specific areas following pediatric TBI. By centering caregiver voices across recovery, this study underscores their unique expertise in identifying system-level gaps and informing the development of interventions, services, and policies that better support children with TBI and their families over time. Full article

Background/Objectives: The aim of this study was to show a standardized four-step technique that can offer individually personalized full-mouth therapy for each complex dental patient with erosive tooth wear resulting from bulimia nervosa, focusing on the individualized vertical dimension of occlusion (VDO), functional and aesthetic stability, and patient-reported outcomes, including dental symptoms, nutrition, self-perception, and quality of life. Methods: The following steps are proposed for structured full-mouth rehabilitation. Step 1: Intraoral diagnosis via a single computer-aided impression. Step 2: Determination of a new adequate vertical dimension of occlusion and soft tissue prediction. Step 3: Removable sample dentures—prototypes. Step 4: Non-prep/minimal-prep crowns as the long-term provisional/definitive treatment. Results: Nine adults (11% male) with dental erosion caused by bulimia nervosa (78%), gastro-esophageal reflux (11%), and soft drinks (11%) were part of this cohort. The novel digital workflow enabled restoration of an individualized vertical dimension of occlusion, stable occlusion, appropriate centric and eccentric contacts, biomimetic dental anatomy, harmonious tooth proportions, and optimized red–white aesthetics. Dental problems (hypersensitivity, dental pain), nutritional behavior, body perception, and quality of life improved after the full-mouth rehabilitation. Conclusions: The presented digital workflow offers a promising approach for full-mouth rehabilitation in patients with severe dental erosion, particularly associated with bulimia nervosa, enabling structured restoration planning and stepwise evaluation of the vertical dimension of occlusion and functional adaptation. Prospective studies with larger cohorts are needed to confirm long-term clinical outcomes and patient-reported benefits. Full article

Glycosylation is the most common post-translational modification in the human proteome, with over half of all human proteins bearing covalently attached glycans. These glycan structures direct protein folding through ER quality control machinery, shield polypeptides from proteolytic degradation, regulate circulatory half-life via the asialoglycoprotein receptor, and serve as molecular signals for immune recognition and intracellular trafficking. For biopharmaceuticals, which constitute a rapidly growing share of approved drugs, glycan profiles are critical quality attributes that directly determine clinical efficacy and safety. Yet achieving the correct glycosylation on a therapeutic protein remains one of the field’s central challenges, as glycan biosynthesis is non-template-driven and highly sensitive to expression system and manufacturing conditions. This review connects the biological functions of glycosylation to the practical strategies of glycoengineering, examining how sequence design, expression system selection, and downstream enzymatic remodeling are used to optimize therapeutic glycoproteins. Clinical case studies spanning monoclonal antibodies, cytokines, and enzyme replacement therapies illustrate how glycan engineering translates into improved patient outcomes. We conclude by surveying emerging technologies poised to make precisely glycosylated therapeutics more accessible. Full article

Background: Atopic dermatitis is a chronic inflammatory skin disease in children, frequently associated with skin barrier dysfunction, immune dysregulation, and dysbiosis. Infected, treatment-resistant lesions may increase disease severity and complicate management, particularly in the presence of Staphylococcus aureus colonization. Objectives: To characterize the microbiological profile of infected, non-responsive pediatric atopic dermatitis, evaluate short-term clinical outcomes following individualized treatment, and identify predictors of disease severity. Methods: This observational analytical study included 41 children with atopic dermatitis recruited at Saint Constantin Hospital, Brașov, Romania, between September 2025 and February 2026. Eligible patients fulfilled the Hanifin and Rajka criteria and presented with infected, treatment-resistant lesions. Skin cultures were subjected to an antibiogram and antifungigram. Disease severity was assessed using the Patient-Oriented Eczema Measure (POEM) and SCORAD at baseline, 7 days, and 30 days. Repeated-measures ANOVA, mixed ANOVA, and hierarchical linear regression were used for statistical analysis. Results: Staphylococcus aureus was the predominant pathogen, followed by other bacterial species. Both POEM and SCORAD scores improved significantly over the 30-day follow-up, with marked improvement after 7 days and further reduction by day 30. Although patients with S. aureus colonization and those receiving systemic therapy tended to have higher disease severity, neither factor significantly influenced the trajectory of clinical improvement. Baseline disease severity was the strongest predictor of 30-day POEM and SCORAD outcomes, whereas demographic and perinatal characteristics did not independently predict short-term clinical outcomes. Conclusions: Individualized management was associated with significant improvements in clinician-assessed disease severity and patient-reported symptoms during the 30-day follow-up. Staphylococcus aureus, particularly methicillin-sensitive S. aureus (MSSA), was the most frequently isolated pathogen. Baseline disease severity was the strongest predictor of short-term clinical outcomes, whereas the evaluated demographic and perinatal characteristics did not provide additional predictive value in this cohort. Larger prospective controlled studies are needed to confirm these findings. Full article